Project Summary Vascular reconstructions, such as angioplasty and bypass, often fail due to neointimal hyperplasia (IH) that re- narrows the vessel lumen. Dysfunctional smooth muscle cells (SMCs) are the major constituents of the neointimal lesion; dysfunction of adjacent endothelial cells (ECs) not only contributes to IH but also promotes thrombosis or clotting. The current clinical method for IH-attenuation relies on anti-proliferative drugs and delivery with a stent implanted following angioplasty. As both the drug (e.g., rapamycin) and stenting promote EC dysfunction, the clinical outcome of drug-eluting stents is compromised and also complicated by thrombogenic risks. It has been a paramount challenge to solve this major medical problem as it requires innovations in both drug and delivery methods. We have made an exciting preliminary finding: inhibition of a stress-response kinase called PERK abrogates both SMC and EC dysfunction, and effectively mitigates IH, without affecting endothelial repair of denuded arteries in a preclinical angioplasty model. Our central hypothesis is that PERK is a common target driving dysfunction of not only SMCs but also ECs. We further expect that stent-free delivery of PERK inhibitor will provide an endothelium-protective approach for the safe and effective treatment of IH. Therefore, in Specific Aim-1, we will define a common molecular target that promotes dysfunction in both SMCs and ECs during IH. To this end, we have identified PERK as a lead target, the inhibition of which mitigates dysfunction of both cell types and IH. In Specific Aim-2, we will develop a stent-free therapeutic strategy via targeted endovascular delivery to mitigate IH. For this aim, we have created a prototype biomimetic nanoplatform to achieve stent-free delivery of PERK inhibitor targeted to injured arteries where IH occurs. This is a paradigm-shifting proposal because it conflates innovations in both drug and drug delivery strategies aimed at improving treatment for IH. In contrast to the status quo drug (rapamycin) which is EC- toxic, PERK inhibition blocks both SMC dysfunction (proliferation and de-differentiation) and EC dysfunction (impaired growth and thrombogenesis). Moreover, drastically different from the current stenting method, stent- free endovascular delivery of PERK inhibitor will be achieved using biomimetic nanoclusters (coated with biological membranes) that effectively home in on injured arteries. The ultimate product of this research will be a non-thrombogenic/stent-free new therapeutic paradigm for the safe and effective treatment of IH. Such treatment is expected to significantly reduce the mortality, morbidity, and tremendous costs among millions of patients in the US who are predisposed to IH-associated occluding vascular diseases. 1